Knowledge, attitude, and practice of Egyptian medical students towards healthcare workers' recommended vaccines: a nationwide cross-sectional survey.

BACKGROUND: Vaccination of healthcare workers (HCWs) is pivotal in decreasing the incidence of contagious infections in hospital settings. In this study, we assessed the knowledge, attitude, and practice regarding HCWs' recommended vaccines among medical students and interns in Egypt. METHODS: A multicenter, cross-sectional study was conducted using a structured, pilot-tested, and self-administered questionnaire among Egyptian medical students and interns. We invited 1332 participants to our survey using a systematic random sampling that included participants across nine medical schools in Egypt during the 2021-2022 academic year. RESULTS: Out of 1332 participants, 1141 completed our questionnaire with a response rate of 85.7%. Overall, 43% of the participants had intermediate knowledge (knew 2-3 HCWs' recommended vaccines). Furthermore, 36.7% had received a booster dose of at least one of the HCWs' recommended vaccines over the last 10 years, with only 6.1% having received all recommended vaccines. Hepatitis B vaccine was the most widely known (71%) and received (66.7%). Interns were more likely to know, receive, and recommend HCWs' recommended vaccines. The majority (> 90%) agreed that vaccination is beneficial and safe, with a median score of eight (interquartile range [IQR: Q25-Q75]: 7-9) out of ten for vaccine efficacy and eight (IQR: 7-8) for safety. However, the median score for hesitancy was five (IQR: 2-7). The most common influential and limiting factors for vaccination were scientific facts (60.1%) and fear of vaccine side effects (44.9%). CONCLUSION: Although medical students in Egypt have good knowledge of and attitudes towards vaccination, there is a gap in their practices. Interventions are needed to improve vaccination uptake among medical students in Egypt.

Berberine loaded thermosensitive lipid nanoparticles: in vitro characterization, in silico study, and in vivo anti-arthritic effect.

Thermoresponsive drug delivery systems have been used to treat diseases that cause hyperthermia or elevated body tissue temperatures, viz., rheumatoid arthritis and different cancers. The aim of the study was to enhance berberine (BER) release using thermosensitive nanostructured lipid carriers (TNLCs) through intra-articular administration for the management of arthritis. TNLCs were prepared using binary mixtures of stearic acid and decanoic acid as solid and liquid lipids, respectively. Lipid mixtures with an optimum melting point were assessed using differential scanning calorimetry studies. In vitro characterization of the BER TNLCs included particle size, zeta potential, entrapment efficiency, and drug release at 37 °C and 41 °C. Joint diameter measurement, real-time polymerase chain reaction (RT-PC) analysis, enzyme-linked immunosorbent assay (ELISA) for inflammatory markers, and histological evaluation of the dissected joints were all performed in vivo on rats with adjuvant-induced arthritis. In vitro characterization revealed negatively charged BER-loaded TNLCs with a spherical shape, particle size less than 500 nm, BER entrapment efficiency up to 79%, and a high drug release rate at an elevated temperature of 41 °C. In silico studies revealed the affinity of BER to different formula components and to the measured biomarkers. In vivo assessment of the optimum TNLCs showed that BER TNLCs were superior to the BER solution suspension regarding their effect on inflammatory biomarkers, joint diameter, and histological studies.

Evaluating the efficacy of Nd:YAG fourth harmonic (266 nm) in comparison with ArF excimer (193 nm) in laser corneal reshaping: ex vivo pilot study.

PURPOSE: Laser corneal reshaping is a common eye surgery utilized to overcome many vision disorders. Different UV laser wavelengths can be effective in the treatment. However, the ArF excimer laser (193 nm) is the most commonly used due to its high absorption in the cornea. In the current study, we investigate the efficacy of applying a solid-state laser (Nd:YAG fourth harmonic at 266 nm) for the corneal reshaping procedure. METHODS: The utilized laser is generated using an optical setup based on a BBO nonlinear crystal which converts the Q-switched laser (532 nm) to its fourth harmonic (266 nm). Different pulse energies were applied with the same number of the shoots on ex vivo rabbit corneas, and the histological effect is studied. Moreover, the possible thermal damage on the treated corneal tissues was inspected via electron microscope. Additionally, the DNA damage on the corneal cells due to the application of the proposed laser was examined and compared with the existing technology (ArF Excimer laser at 193 nm) using the comet assay. RESULTS: The histological examination revealed an appropriate ablation result with the minimum thermal effect at 1.5 mJ and 2.0 mJ. The overall results show that applying 50-shoots of the 1.5-mJ pulse energy using the proposed 266-nm solid-state laser produces the optimum ablation effect with the minimum thermal damage, and almost the same DNA damage occurred using the commercial 193-nm ArF excimer laser. CONCLUSION: Solid-state laser at 266 nm could be a good alternative to the common 193-nm excimer laser for corneal reshaping procedures.

Spine surgery under awake spinal anesthesia: an Egyptian experience during the COVID-19 pandemic.

OBJECTIVE: Despite tremendous advancements in biomedical science and surgical technique, spine surgeries are still associated with considerable rates of morbidity and mortality, particularly in the elderly. Multiple novel techniques have been employed in recent years to adequately treat spinal diseases while mitigating the perioperative morbidity associated with traditional spinal surgery. Some of these techniques include minimally invasive methods and novel anesthetic and analgesic methods. In recent years, awake spine surgery with spinal anesthesia has gained attention as an alternative to general anesthesia (GA). In this study, the authors retrospectively reviewed a single-institution Egyptian experience with awake spine surgery using spinal anesthesia during the COVID-19 pandemic. METHODS: Overall, 149 patients who were admitted to As-Salam International Hospital in Cairo for lumbar and lower thoracic spine surgeries, between 2019 and 2020, were retrospectively reviewed. Patient demographics and comorbidities were collected and analyzed. Visual analog scale (VAS) and Oswestry Disability Index (ODI) scores were assessed at different time intervals including preoperatively, immediately after surgery, and 1 year postoperatively. Patient satisfaction was queried through a questionnaire assessing patient preference for traditional anesthesia or spinal anesthesia. RESULTS: Of the 149 patients who successfully received spine surgery with spinal anesthesia, there were 49 males and 100 females. The cohort age ranged from 22 to 85 years with a mean of 47.5 years. The operative time ranged from 45 to 300 minutes with a mean estimated blood loss (EBL) of 385 ± 156 mL. No major cardiopulmonary or intraoperative complications occurred, and patients were able to eat immediately after surgery. Patients were able to ambulate without an assistive device 6 to 8 hours after surgery. Decompression and fusion patients were discharged on postoperative days 2 and 3, respectively. VAS and ODI scores demonstrated excellent pain relief, which was maintained at the 1-year postoperative follow-up. No 30- or 90-day readmissions were recorded. Of 149 patients, 124 were satisfied with spinal anesthesia and would recommend spinal anesthesia to other patients. The remaining patients were not satisfied with spinal anesthesia but reported being pleased with their postoperative clinical and functional outcomes. One patient was converted to GA due to the duration of the procedure. CONCLUSIONS: Patients who received spinal anesthesia for awake spine surgery experienced short stays in the hospital, no readmissions, patient satisfaction, and well-controlled pain. The results of this study have validated the growing body of literature that demonstrates that awake spine surgery with spinal anesthesia is safe and associated with superior outcomes compared with traditional GA. Additionally, the ability to address chronic debilitating conditions, such as spinal conditions, with minimal use of valuable resources, such as ventilators, proved useful during the COVID-19 pandemic and could be a model should other stressors on healthcare systems arise, especially in developing areas of the world.

Chronic Electroconvulsive Therapy May Induce Calvarial Hyperemia and Marrow Replacement.

ABSTRACT: Electroconvulsive therapy (ECT) is a treatment option for a number of psychiatric disorders, including refractory major depression and obsessive compulsive disorder. There are no known structural sequelae of ECT. Here we present a patient with severe refractory obsessive compulsive disorder and major depression treated over 2 years with ECT every 2 weeks. Planning magnetic resonance imaging intended for a potential procedural intervention for her psychiatric disease incidentally demonstrated a new area of increased enhancement and loss of marrow signal within the right frontal bone. Imaging findings were suggestive of underlying bone marrow or bone changes, although there was no evidence of bone destruction on bone-windowed computed tomography (CT) and there was no uptake on nuclear bone scan. The CT chest/abdomen/pelvis were also reassuring that this did not represent metastatic disease, and findings were unchanged on repeat magnetic resonance imaging 4 months later. Thus, this area corresponded to the site directly underlying the unilateral ECT electrode placement, suggestive of never-before described ECT-induced hyperemia. We report for the first time that frequent, chronic ECT may induce asymptomatic skull bone marrow hyperemia with radiologic findings. This appears to be a direct consequence of electrical current leading to chronic inflammatory and edematous marrow replacement. Electroconvulsive therapy should be added to the neuroradiological differential diagnosis of calvarial enhancement and loss of marrow signal. Psychiatrists should counsel patients on the possibility of this rare radiological finding, which may be confused for other processes.

An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.

PURPOSE: Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae. METHODS: Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab. RESULTS: After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration. CONCLUSION: This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.

Systematic review of spontaneous splenic rupture in dengue-infected patients.

Dengue infection varies from a mild febrile form to more severe disease with plasma leakage, shock, and multiorgan failure. Several serious complications such as cardiomyopathy, encephalopathy, encephalitis, hepatic damage, and neural manifestations cause organ damage in dengue infection. Splenic rupture, a less well known but life-threatening complication, can occur in dengue. The mechanism of splenic rupture in dengue is still unclear. Optimal therapeutic management is required to save the lives of patients with this complication. The objective of this study was to conduct a systematic review of studies documenting the development of spontaneous nontraumatic splenic rupture in patients with dengue infection. In March 2018, a search was conducted systematically in nine electronic databases, in addition to hand- searching. A total of 127 references were exported to Endnote; 47 references remained after removing duplicates. Finally, 16 reports met the inclusion criteria and represented 17 cases. All articles were evaluated and data extracted according to predefined criteria: number of cases, age, sex, severity of dengue disease, days of illness before admission, methods of definitive diagnosis, timing of the event, and management and outcome. A total of 17 individual patients including 13 males and four females were found. Most of the patients were young adults (ranging from 20 to 52 years) and diagnosed with computed tomography scan and managed with splenectomy. Four cases were fatal. Pathological splenic rupture in dengue is a rare, life-threatening condition where timely management can achieve a favorable outcome.

Protective Role of Casuarinin from Melaleuca leucadendra against Ethanol-Induced Gastric Ulcer in Rats.

Gastric ulcer is a major health problem. Current treatment options of gastric ulcer, including antagonists of histamine H2 receptor and inhibitors of the proton pump, do not cure gastric ulcers, but only provide temporary relief of symptoms and can be associated with severe side effects. The lack of effective and safe medications for this global health problem urges for the discovery of novel classes of compounds with potent activity and an acceptable safety profile. Ethanol-induced ulceration in rats was used to evaluate the gastroprotective activity of casuarinin, an ellagitannin isolated from Melaleuca leucadendra. Casuarinin (25, 50, and 100 mg/kg) reduced the ulcer area by 45, 78, and 99%, respectively, compared with the ulcer group. Casuarinin (100 mg/kg) increased mucin content by 1.8-fold and reduced acidity by 42%. At the same dose, it also increased the levels of reduced glutathione by 194%, catalase by 586%, and prostaglandin E2 to its normal level. In contrast, it attenuated the ethanol-increased levels of malondialdehyde by 56%, TNF-α by 58%, and caspase-3 by 87%. Histological findings demonstrated that casuarinin exhibited a protective effect against tissue alterations in response to the ethanol-induced ulcer. Casuarinin suppressed the immunoexpression of nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase to their normal values. It also induced the expression of heat shock protein-70, reaching up to 4.9-fold in comparison with the ulcer group. The potent gastroprotective effect of casuarinin was thus attributed to its anti-inflammatory, antioxidant, and antiapoptotic effects. Our results suggest the potential application of casuarinin as an antiulcer agent from natural sources.

The short-term impact of COVID-19 pandemic on spine surgeons: a cross-sectional global study.

PURPOSE: The outbreak of COVID-19 erupted in December 2019 in Wuhan, China. In a few weeks, it progressed rapidly into a global pandemic which resulted in an overwhelming burden on health care systems, medical resources and staff. Spine surgeons as health care providers are no exception. In this study, we try to highlight the impact of the crisis on spine surgeons in terms of knowledge, attitude, practice and socioeconomic burden. METHODS: This was global, multicentric cross-sectional study on 781 spine surgeons that utilized an Internet-based validated questionnaire to evaluate knowledge about COVID-19, availability of personal protective equipment, future perceptions, effect of this crisis on practice and psychological distress. Univariate and multivariate ordinal logistic regression analyses were used to evaluate the predictors for the degree of COVID-19 effect on practice. RESULTS: Overall, 20.2%, 52% and 27.8% of the participants were affected minimally, intermediately and hugely by COVID-19, respectively. Older ages (ß = 0.33, 95% CI 0.11-0.56), orthopedic spine surgeons (ß = 0.30, 95% CI 0.01-0.61) and those who work in the private sector (ß = 0.05, 95% CI 0.19-0.61) were the most affected by COVID-19. Those who work in university hospitals (ß = - 0.36, 95% CI 0.00 to - 0.71) were affected the least. The availability of N95 masks (47%) and disposable eye protectors or face shields (39.4%) was significantly associated with lower psychological stress (p = 0.01). Only 6.9%, 3.7% and 5% had mild, moderate and severe mental distress, respectively. CONCLUSION: While it is important to recognize the short-term impact of COVID-19 pandemic on the practice of spine surgery, predicting where we will be standing in 6-12 months remains difficult and unknown. The COVID-19 crisis will probably have an unexpected long-term impact on lives and economies.

Methodological steps used by authors of systematic reviews and meta-analyses of clinical trials: a cross-sectional study.

BACKGROUND: The quality of systematic reviews and meta-analyses (SR/MAs) depends on the extent of the methods used. We investigated the methodological steps used by authors of SR/MAs of clinical trials via an author survey. METHODS: We conducted an email-based cross-sectional study by contacting corresponding authors of SR/MAs that were published in 2015 and 2016 and retrieved through the PubMed database. The 27-item questionnaire was developed to study the methodological steps used by authors when conducting a SR/MA and the demographic characteristics of the respondent. Besides the demographic characteristics, methodological questions regarding the source, extraction and synthesis of data were included. RESULTS: From 10,292 emails sent, 384 authors responded and were included in the final analysis. Manual searches were carried out by 69.2% of authors, while 87.3% do updated searches, 49.2% search grey literature, 74.9% use the Cochrane tool for risk of bias assessment, 69.8% assign more than two reviewers for data extraction, 20.5% use digital software to extract data from graphs, 57.9% use raw data in the meta-analysis, and 43.8% meta-analyze both adjusted and non-adjusted data. There was a positive correlation of years of experience in conducting of SR/MAs with both searching grey literature (P = 0.0003) and use of adjusted and non-adjusted data (P = 0.006). CONCLUSIONS: Many authors still do not carry out many of the vital methodological steps to be taken when performing any SR/MA. The experience of the authors in SR/MAs is highly correlated with use of the recommended tips for SR/MA conduct. The optimal methodological approach for researchers conducting a SR/MA should be standardized.

Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing's disease.

PURPOSE: Hypofractionated stereotactic radiotherapy (HSRT) for refractory Cushing's disease may offer a condensed treatment schedule for patients with large tumors abutting the optic chiasm unsuitable for stereotactic radiosurgery (SRS). To-date only four patients have been treated by HSRT in the published literature. We investigated the feasibility, toxicity, and efficacy of HSRT compared to SRS. METHODS: After approval, we retrospectively evaluated patients treated at our institution for refractory Cushing's disease with SRS or HSRT. Study outcomes included biochemical control, time to biochemical control, local control, and late complications. Binary logistic regression and Cox proportional hazards regression evaluated predictors of outcomes. RESULTS: Patients treated with SRS (n = 9) and HSRT (n = 9) were enrolled with median follow-up of 3.4 years. Clinicopathologic details were balanced between the cohorts. Local control was 100% in both cohorts. Time to biochemical control was 6.6. and 9.5 months in the SRS and HSRT cohorts, respectively (p = 0.6258). Two patients in each cohort required salvage bilateral adrenalectomy. Late complications including secondary malignancy, radionecrosis, cranial nerve neuropathy, and optic pathway injury were minimal for either cohort. CONCLUSIONS: HSRT is an appropriate treatment approach for refractory Cushing's disease, particularly for patients with large tumors abutting the optic apparatus. Prospective studies are needed to validate these findings and identify factors suggesting optimal fractionation approaches.

Hepatoprotective activity of praecoxin A isolated from Melaleuca ericifolia against carbon tetrachloride-induced hepatotoxicity in mice. Impact on oxidative stress, inflammation, and apoptosis.

The hepatoprotective activity of praecoxin A, an ellagitannin from Melaleuca ericifolia, was determined against CCl4 -induced toxicity in mice. Praecoxin A was administered (25, 50, and 100 mg/kg) for 5 days followed by CCl4 . Praecoxin A markedly ameliorated the CCl4 -induced increase in AST (by 19, 52, and 56%), ALP (22, 45, and 48%), ALT (11, 47, and 54%), total bilirubin (14, 27, and 28%), and MDA (26, 44, and 51%) at the tested doses, respectively, as compared with CCl4 group. It was evident that praecoxin A significantly (p < 0.001) increased the antioxidant parameters GSH (45, 99, and 137%) and SOD (61, 129, and 159%). Histological findings revealed a marked amelioration of hepatocyte degeneration, necrosis, inflammatory cell infiltration, and hemorrhage in the groups treated with praecoxin A. COX-2 and caspase-3 hepatic expressions were significantly downregulated (p < 0.001) in praecoxin A-treated groups (up to 57, 83, and 93% for COX-2 and by 30, 82, and 99% for caspase-3). These findings suggest that praecoxin A exerts a beneficial effect against oxidative stress by reducing lipid peroxidation, enhancing the antioxidant defense status, and protecting against the histopathological changes induced by CCl4 . This study highlights a promising natural hepatoprotective candidate derived from M. ericifolia that might be an alternative to silymarin.

Production and recovery of poly-3-hydroxybutyrate bioplastics using agro-industrial residues of hemp hurd biomass.

The present study describes production and recovery of poly(3-hydroxybutyrate) P(3HB) from agro-industrial residues. Production was conducted using Ralstonia eutropha strain with hemp hurd biomass hydrolysates sugars as a carbon source and ammonium chloride as the nitrogen source. Results show that maximum hydrolysis yield of 72.4% was achieved with total sugar hydrolysate concentration (i.e., glucose and xylose) of 53.0 g/L. Sugar metabolism by R. eutropha showed preference for glucose metabolism over xylose. Under optimum conditions, cells can accumulate P(3HB) polymer in quantity up to 56.3 wt% of the dry cell weight. This corresponds to total production of 13.4 g/L (productivity of 0.167 g/L h). Nitrogen source showed no adverse effect on P(3HB) biosynthesis, but rather on cell growth. Among several examined recovery techniques, ultrasonic-assisted sodium dodecyl sulfate (SDS) recovered bioplastic directly from the broth cell concentrate with P(3HB) content of 92%. Number average molecular weights (Mn) of final recovered bioplastic were in the range of 150-270 kDa with polydispersity index (Mw/Mn) in the range of 2.1-2.4.

A simple technique for easier anterior odontoid screw fixation.

BACKGROUND: Anterior odontoid screw fixation (AOSF) is an osteosynthetic technique used for fixation of type 2 and rostral type 3 odontoid fractures. Compared to other treatment modalities, it provides immediate stability, preservation of the majority of the remaining C1-2 motion and an achieved union rate of 80-100%. AOSF requires a stable and reduced odontoid to allow for placement of guide wire and cannulated screw. Image guidance with neuro-navigation or intraoperative fluoroscopy are used for accurate placement of instrumentation. Minimally invasive techniques have been described, such as endoscopic or percutaneous placement of odontoid screws and the use of tubular retractor system. Major site-specific complications include neural injury, esophageal or pharyngeal perforation, hemorrhage, and airway obstruction. PURPOSE: To assess safety and efficacy of a new simple technique developed by the Authors for insertion of the odontoid screw through a less invasive anterior approach. STUDY DESIGN: Prospective case series Methods: Eight patients, 7 males, with odontoid fractures were treated with AOSF under fluoroscopic guidance between January 2014 and October 2015. The operation was successfully completed without technical difficulties using a beveled bone marrow biopsy needle (Jamshidi needle) as a sleeve for guide wire insertion. RESULTS: No soft tissue complications such as esophageal or neuro-vascular injury occurred. Intraoperative bleeding was 25 mL on average. The operation time averaged 75 min. All of the screws were placed in good positions. After a mean follow-up of 12.1 months (range 8-18 months), radiographic fusion was documented for 7 of 8 patients (87.5%). Neither clinical complications nor hardware loosening or breakage occurred. CONCLUSION: Our short term clinical results suggest that the new less invasive anterior odontoid screw fixation procedure using a Jamshidi needle and fluoroscopy is technically easy with good clinical and radiological results.

An optimised spectrophotometric assay for convenient and accurate quantitation of intracellular iron from iron oxide nanoparticles.

We report the development and optimisation of an assay for quantitating iron from iron oxide nanoparticles in biological matrices by using ferene-s, a chromogenic compound. The method is accurate, reliable and can be performed with basic equipment common to many laboratories making it convenient and inexpensive. The assay we have developed is suited for quantitation of iron in cell culture studies with iron oxide nanoparticles, which tend to manifest low levels of iron. The assay was validated with standard reference materials and with inductively coupled plasma-mass spectrometry (ICP-MS) to accurately measure iron concentrations ∼1 × 10-6 g in about 1 × 106 cells (∼1 × 10-12 g Fe per cell). The assay requires preparation and use of a working solution to which samples can be directly added without further processing. After overnight incubation, the absorbance can be measured with a standard UV/Vis spectrophotometer to provide iron concentration. Alternatively, for expedited processing, samples can be digested with concentrated nitric acid before addition to the working solution. Optimization studies demonstrated significant deviations accompany variable digestion times, highlighting the importance to ensure complete iron ion liberation from the nanoparticle or sample matrix to avoid underestimating iron concentration. When performed correctly, this method yields reliable iron ion concentration measurements to ∼2 × 10-6 M (1 × 10-7 g/ml sample).

Time to diagnosis of pediatric brain tumors: a report from the Pediatric Hematology and Oncology Center in Rabat, Morocco.

OBJECTIVE: Delayed diagnosis of pediatric brain tumors is known to occur worldwide but is not well studied in developing countries. Here, we examined the extent of delayed pediatric brain tumor diagnoses in Rabat, Morocco, and consider its potential causes and possible solutions. METHODS: We conducted a survey and interviews of the parents of children who were admitted to the Department of Hematology and Pediatric Oncology of Rabat Children's Hospital from January 1, 2016 to June 30, 2016. RESULTS: The families of 27 patients (14 girls and 13 boys) participated in the survey and interview. The median patient age was 7 years (range, 1-15 years). The most common presenting symptoms were vomiting (n = 18) and headache (n = 17). The tumor locations were supratentorial in 13 cases and infratentorial in 14 cases. The median time to diagnosis was 2 months (range, 0.25-20 months). The longest times to diagnosis occurred in children older than 5 years and in patients with supratentorial tumors or low-grade glioma. We did not observe any differences in the time to diagnosis according to sex, socioeconomic status, or urban or rural origin. CONCLUSIONS: Delayed diagnosis of pediatric brain tumors is a universal problem, evidenced by many studies in different countries. We propose that a paradigm shift in medical curricula addressing the delayed diagnosis of pediatric brain tumors should occur in medical schools and clinical training programs.

GSTP1 Loss results in accumulation of oxidative DNA base damage and promotes prostate cancer cell survival following exposure to protracted oxidative stress.

BACKGROUND: Epigenetic silencing of glutathione S-transferase π (GSTP1) is a hallmark of transformation from normal prostatic epithelium to adenocarcinoma of the prostate. The functional significance of this loss is incompletely understood. The present study explores the effects of restored GSTP1 expression on glutathione levels, accumulation of oxidative DNA damage, and prostate cancer cell survival following oxidative stress induced by protracted, low dose rate ionizing radiation (LDR). METHODS: GSTP1 protein expression was stably restored in LNCaP prostate cancer cells. The effect of GSTP1 restoration on protracted LDR-induced oxidative DNA damage was measured by GC-MS quantitation of modified bases. Reduced and oxidized glutathione levels were measured in control and GSTP1 expressing populations. Clonogenic survival studies of GSTP1- transfected LNCaP cells after exposure to protracted LDR were performed. Global gene expression profiling and pathway analysis were performed. RESULTS: GSTP1 expressing cells accumulated less oxidized DNA base damage and exhibited decreased survival compared to control LNCaP-Neo cells following oxidative injury induced by protracted LDR. Restoration of GSTP1 expression resulted in changes in modified glutathione levels that correlated with GSTP1 protein levels in response to protracted LDR-induced oxidative stress. Survival differences were not attributable to depletion of cellular glutathione stores. Gene expression profiling and pathway analysis following GSTP1 restoration suggests this protein plays a key role in regulating prostate cancer cell survival. CONCLUSIONS: The ubiquitous epigenetic silencing of GSTP1 in prostate cancer results in enhanced survival and accumulation of potentially promutagenic DNA adducts following exposure of cells to protracted oxidative injury suggesting a protective, anti-neoplastic function of GSTP1. The present work provides mechanistic backing to the tumor suppressor function of GSTP1 and its role in prostate carcinogenesis.

Polycomb repressive complex 2 is required for MLL-AF9 leukemia.

A growing body of data suggests the importance of epigenetic mechanisms in cancer. Polycomb repressive complex 2 (PRC2) has been implicated in self-renewal and cancer progression, and its components are overexpressed in many cancers. However, its role in cancer development and progression remains unclear. We used conditional alleles for the PRC2 components enhancer of zeste 2 (Ezh2) and embryonic ectoderm development (Eed) to characterize the role of PRC2 function in leukemia development and progression. Compared with wild-type leukemia, Ezh2-null MLL-AF9-mediated acute myeloid leukemia (AML) failed to accelerate upon secondary transplantation. However, Ezh2-null leukemias maintained self-renewal up to the third round of transplantation, indicating that Ezh2 is not strictly required for MLL-AF9 AML, but plays a role in leukemia progression. Genome-wide analyses of PRC2-mediated trimethylation of histone 3 demonstrated locus-specific persistence of H3K27me3 despite inactivation of Ezh2, suggesting partial compensation by Ezh1. In contrast, inactivation of the essential PRC2 gene, Eed, led to complete ablation of PRC2 function, which was incompatible with leukemia growth. Gene expression array analyses indicated more profound gene expression changes in Eed-null compared with Ezh2-null leukemic cells, including down-regulation of Myc target genes and up-regulation of PRC2 targets. Manipulating PRC2 function may be of therapeutic benefit in AML.

Fenofibrate ameliorates nitroglycerin-induced migraine in rats: Role of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways.

Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability.